Liver Transplantation for Hereditary Transthyretin Amyloidosis: After 20 Years Still the Best Therapeutic Alternative?

BACKGROUND: Until recently, liver transplantation (Ltx) was the only available treatment for hereditary transthyretin (TTR) amyloidosis; today, however, several pharmacotherapies are tested. Herein, we present survival data from the largest available database on transplanted hereditary TTR patients to serve as a base for comparison. METHODS: Liver transplantation was evaluated in a 20-year retrospective analysis of the Familial Amyloidosis Polyneuropathy World Transplant Registry. RESULTS: From April 1990 until December 2010, data were accumulated from 77 liver transplant centers. The Registry contains 1940 patients, and 1379 are alive. Eighty-eight Ltx were performed in combination with a heart and/or kidney transplantation. Overall, 20-year survival after Ltx was 55.3%. Multivariate analysis revealed modified body mass index, early onset of disease (<50 years of age), disease duration before Ltx, and TTR Val30Met versus non-TTR Val30Met mutations as independent significant survival factors. Early-onset patients had an expected mortality rate of 38% that of the late-onset group (P < 0.001). Furthermore, Val30Met patients had an expected mortality rate of 61% that of non-TTR Val30Met patients (P < 0.001). With each year of duration of disease before Ltx, expected mortality increased by 11% (P < 0.001). With each 100-unit increase in modified body mass index at Ltx, the expected mortality decreased to 89% of the expected mortality (P < 0.001). Cardiovascular death was markedly more common than that observed in patients undergoing Ltx for end-stage liver disease. CONCLUSIONS: Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in early-onset TTR Val30Met patients, requires consideration.

Mucosa nasal: un nuevo tejido para el diagnóstico biópsico de amiloidosis hereditaria relacionada con transtirretina / Nasal mucosa: A new site for tissue biopsy to diagnose hereditary TTR amyloidosis

Background and objective: We report 2 carriers of the TTRV30M mutation and its plasmatic biochemical marker with clinical symptoms compatible with hereditary TTR amyloidosis. Materials and methods: Based on our previously reported casual finding of amyloid TTR in nasal mucosa (2008), we requested biopsy of this tissue to search for amyloid with Congo red staining and TTR immunohistochemical analysis. Results: The histological diagnosis was achieved by retrospective analysis of surgical sinonasal biopsy in the first patient and prospective biopsy of inferior nasal concha in the second. Large interstitial deposits of ATTR were observed in both cases. Conclusions: We suggest nasal mucosa as a suitable site for tissue biopsy in patients with suspected hereditary TTR amyloidosis (AU)

Antecedentes y objetivo: Presentamos 2 portadores de la mutación TTRV30M y su marcador bioquímico plasmático, con síntomas sugestivos de amiloidosis hereditaria TTR. Material y métodos: Basándonos en el hallazgo casual de amiloide TTR en la mucosa nasal previamente publicado (2008), indicamos la biopsia de este tejido para la búsqueda de amiloide TTR con tinción Rojo Congo y análisis inmunohistoquímico de TTR. Resultados: El diagnóstico histológico se logró en el primer enfermo con análisis retrospectivo de la biopsia de material operatorio sinonasal, y en el segundo con biopsia prospectiva del cornete nasal inferior. En ambos casos se observaron grandes depósitos intersticiales de amiloide de amiloidosis hereditaria relacionada con transtirretina. Conclusiones: Consideramos que la biopsia de la mucosa nasal es idónea para el diagnóstico de pacientes con sospecha de amiloidosis hereditaria TTR (AU)

Nasal mucosa: a new site for tissue biopsy to diagnose hereditary TTR amyloidosis.

BACKGROUND AND OBJECTIVE: We report 2 carriers of the TTRV30M mutation and its plasmatic biochemical marker with clinical symptoms compatible with hereditary TTR amyloidosis. MATERIALS AND METHODS: Based on our previously reported casual finding of amyloid TTR in nasal mucosa (2008), we requested biopsy of this tissue to search for amyloid with Congo red staining and TTR immunohistochemical analysis. RESULTS: The histological diagnosis was achieved by retrospective analysis of surgical sinonasal biopsy in the first patient and prospective biopsy of inferior nasal concha in the second. Large interstitial deposits of ATTR were observed in both cases. CONCLUSIONS: We suggest nasal mucosa as a suitable site for tissue biopsy in patients with suspected hereditary TTR amyloidosis.

Early diagnosis and management of patients with familial ATTR amyloidosis receiving livers from asymptomatic variant TTR carriers.

The possibility of a patient with familial ATTR amyloidosis receiving a liver from an asymptomatic variant TTR carrier is remote [corrected].However, in 2008, it was reported that this unlikely event occurred in a patient in Portugal. We report our protocol for early diagnosis and management of this entity.

Finding of vascular amyloid TTR in inferior nasal concha in a patient with FAP TTRVal30Met.

We report the case of a female patient with familial amyloid polyneuropathy (FAP) who demonstrated TTR amyloid deposition in the inferior nasal conchal vessels. To our knowledge this location has not been described previously in FAP; in addition, it was detected in a patient who had undergone successful liver transplantation (LTX) 4 years earlier. The amyloid deposition was found incidentally during examination of a right nasal obstruction caused by a nonspecific inflammatory polyp. Small focal deposits of amyloid TTR were observed on deep thick walled vessels, contrasting with the massive deposition reported in neoformed vessels in amyloidomas. This amyloid was clearly deposited between the onset of FAP and LTX and had probably decreased since the graft. If amyloid deposition is frequent in inferior nasal concha in FAP, this location could be a suitable biopsy site.

Familial amyloid polyneuropathy associated with TTRSer50Arg mutation in two Iberian families presenting a novel single base change in the mutant gene.

We present two families, from Spain and Portugal, with familial amyloid polyneuropathy (FAP) associated with the mutation TTRSer50Arg. This mutation was first described in two Japanese patients from independent families and later in a French-Italian patient and a Vietnamese family. The two families presented here, are the first to be diagnosed with this mutation in the Iberian Peninsula. In the patients of both families, FAP was very aggressive as they rapidly developed multiple symptoms with progressive deterioration; we emphasize the presence of severe orthostatic hypotension in the Spanish proband which confined him to a wheelchair. This proband was the first patient with this mutation to have undergone liver transplantation and results were encouraging. The mutation was detected in four patients and one disease-free relative by DNA sequencing of exon 3 and induced mutation restriction analysis. The most outstanding feature was the single base transversion A to C in codon 50 (CGT instead of AGT), whereas in both Japanese patients and the French-Italian patient it was T to G (AGG instead of AGT). To our knowledge only six FAP mutations with more than one single nucleotide mutation for the same codon have been reported to date.

Genetic epidemiology of familial amyloid polyneuropathy in the Balearic Islands (Spain).

Between 1976 and 2003, we diagnosed 144 patients with familial amyloid polyneuropathy (FAP) in the Balearic Islands (Spain). Analysis of genetic epidemiological data from 102 confirmed patients showed 62% were men. Parental transmission was paternal in 38, maternal in 25, and unknown in 39. No family history of FAP was found in 32 patients. TTRVal30Met associated with haplotype I was present in the individuals studied. Mean age-at-onset was 45.7 years which lies between that of Sweden and those of Portugal, Japan and Brazil. Duration of FAP was of 9.7 years. Age-at-onset, age-at-death, duration and fertility were similar between sexes. Twenty-nine intergeneration familial pairs of patients were ascertained. Raw anticipation was positive in twenty-four pairs, zero in one, and negative in four. Differences greater than 9 years between age-at-onset of the first and second member were considered relevant; positive relevant anticipation was found in 76% of the whole pairs. The frequency of positive anticipation of parent-child pairs was not significantly different than those described in the Swedish and Portuguese series. Significant positive correlation in age-at-onset was confirmed in twenty-seven types of pairs supporting the hypothesis that a genetic factor may modulate age-at-onset. The Balearic focus of FAP is expanding and constitutes a public health problem.

Polineuropatía amiloidótica familiar 2003 / Familial amyloid polyneuropathy 2003

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First Spanish family with familial amyloidotic polyneuropathy associated to TTR Thr49Ile mutation.

We present a Spanish patient with familial amyloidotic polyneuropathy associated with the TTR Thr49Ile mutation previously described in a Japanese patient. This is the first report in a Caucasian patient and the second in the literature. Age of onset at 66 and the clinical picture were similar to the Japanese patient: sensorimotor polyneuropathy, digestive autonomic disturbances, cardiomyopathy and loss of weight. The mutation was diagnosed by DNA sequencing and induced mutation restriction analysis.

Trasplante hepático dominó o secuencial: descripción de los tres primeros pacientes en España / Sequential liver transplantation: description of the first three patients in Spain

Fundamento: El trasplante hepático dominó o secuencial (DTXH) es un tipo de injerto de donante vivo propuesto en 1993 y realizado por primera vez en 1995; posteriormente se han publicado más de 45. El hígado de un paciente con polineuropatía amiloidótica familiar (PAF) se implanta a un enfermo mayor de 60 años afectado de un proceso hepático generalmente neoplásico, porque el hígado de esos donantes es normal desde el punto de vista anatómico y funcional, salvo la síntesis de la variante sistémica de la transtirretina (TTR), que sólo podría originar la PAF en el receptor al cabo de un período mayor de 8 años. Pacientes y método: Se presentan los tres primeros casos de DTXH realizados en España. Los donantes eran pacientes con PAF con variante TTRMet30 procedentes del foco mallorquín. El primero de los receptores presentaba un gravísimo hiperinsulismo debido a metástasis hepáticas de insulinoma maligno; los otros dos tenían hepatocarcinoma implantado sobre hígado cirrótico. Resultados: En el postoperatorio de los receptores, la función del hígado fue perfecta, y desapareció inmediatamente el hiperinsulinismo en el primero; éste falleció a los 10 días por sepsis, mientras que los otros siguen con función hepática normal, sin recidiva neoplásica ni inicio de PAF. En los donantes, la evolución fue normal, con perfecta función hepática. Conclusiones: Nuestros datos, coincidentes con los publicados, permiten concluir que el DTXH es un método válido para un determinado grupo de pacientes. Además, aumenta el contingente de donantes hepáticos y, por consiguiente, disminuyen las sobrecargadas listas de espera (AU)